Expanding HSCs by blocking ferroptosis
Background
Hematopoietic stem cell (HSC) transplant is a common life-saving treatment for several hematological and immunological disorders, including leukemia, bone marrow failure syndromes, and immunodeficiencies. To date, over 1.5 million HSC transplants have been performed, making it a widespread therapeutic approach. However, one of the major limitations of this treatment is the limited number of available HSCs for transplant. Many patients face significant challenges in finding a suitable donor, and the viable HSCs collected may not be sufficient for a successful transplant. Currently, HSC transplantation relies almost entirely on donor-derived cells, obtained from bone marrow, peripheral blood, or umbilical cord blood. Moreover, the current methods used for expanding HSCs do not fully prevent HSC differentiation, leading to loss of function, partially due to a regulated cell death known as ferroptosis.
Developing methods to efficiently harvest and expand HSCs ex vivo before transplant, while maintaining them in a non-differentiated state, would significantly improve patient outcomes and increase accessibility for more patients.
Technology Overview
A team at Boston Children’s Hospital has advanced our understanding of the role of ferroptosis in maintaining and expanding HSCs. By utilizing liproxstatin-1, a small molecule that inhibits ferroptosis, the team demonstrated an increased capacity to expand human HSCs using different methods without inducing any aberrant hematopoiesis or genotoxicity. The team showed that human HSCs treated with liproxstatin-1 display increased ribosome biogenesis and cholesterol biosynthesis, accompanied by elevated 7-dehydrocholesterol levels, a potent endogenous inhibitor of ferroptosis. In addition, they demonstrated the efficiency of controlling ferroptosis to enhance human HSC expansion through direct genome modifications, confirming the role of ferroptosis and opening a new path for clinical applications.
Applications
- Treatments of hematological and immunological disorders.
Advantages
- Increased efficiency of treatment by minimizing HSC differentiation
- Increased accessibility for more patients
- Reduction of transplant costs by maintaining HSCs for longer periods
